The 4th Edition of the Head and Neck WHO Blue Book: Editor’s Perspectives

Adel K. El-Naggar MD, PhD, John Chan MBBS, FRCPath, FRCPA,

Takashi Takata DDS, PhD, Jennifer Grandis MD, Pieter Slootweg MD,DMD,
PhD

PII: S0046-8177(17)30171-5
DOI: doi: 10.1016/j.humpath.2017.05.014
Reference: YHUPA 4233

To appear in: Human Pathology

Received date: 3 April 2017

Revised date: 26 April 2017
Accepted date: 10 May 2017

Please cite this article as: El-Naggar Adel K., Chan John, Takata Takashi, Grandis
Jennifer, Slootweg Pieter, The 4th Edition of the Head and Neck WHO Blue Book:
Editor’s Perspectives, Human Pathology (2017), doi: 10.1016/j.humpath.2017.05.014

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Elsevier Editorial System(tm) for Human

Pathology
Manuscript Draft

Manuscript Number: YHUPA-D-17-00262R1

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Title: The 4th Edition of the Head and Neck WHO Blue Book: Editor's
Perspectives

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Article Type: Editorial (Invitation Only)

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Keywords: Head and neck tumors; tumor classification; World Health
Organization; International organization for Research on Cancer

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Corresponding Author: Dr. Adel K El-Naggar, MD, PhD

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Corresponding Author's Institution: M.D.Anderson Cancer Center

First Author: Adel K El-Naggar, MD, PhD

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Order of Authors: Adel K El-Naggar, MD, PhD; John KC Chan, MBBS, FRCPath,
FRCPA; Takashi Takata, DDS, PhD; Jennifer R Grandis, MD; Pieter J
Slootweg, MD, DMD, PhD
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*Revised Manuscript

The 4th Edition of the Head and Neck WHO Blue Book: Editor’s Perspectives

Adel K. El-Naggar, John Chan, Takashi Takata, Jennifer Grandis, Pieter Slootweg

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In the 4th Edition of the World Health Organization (WHO) Classification of Head and Neck

tumors [1], the editors were committed to maintain the familiar classification and nomenclature of

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previous editions while updating and introducing new entities [2]. At the outset, the editors agreed

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to exclude themselves from authoring or co-authoring any chapters others than Introduction to

their respective Chapters, wherein approaches and modifications where to be highlighted. Broadly,
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efforts were exercised to reduce redundancy by limiting multiple discussions of the same entities to

their commonest anatomic sites. As an example, at squamous mucosal lined sites squamous cell
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carcinoma comprised the main topic, while salivary gland, lymphoreticular, soft tissue and bone

tumors were briefly discussed and the reader is directed to the main text for complete review.
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Similarly, tumors of bone, cartilage and odontogenic origins were addressed in the Odontogenic
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and Maxillofacial bone tumors chapter.

To simplify classification of rare entities occurring at different anatomic sites while

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acknowledging the imperfect and arbitrary nature of this process, a consensus was reached to place

them with common tumors of similar cellular composition. Categories that fell in this topic included

giant cell-forming lesions and granular cell tumors, and were presented at the most frequent site of

their occurrence. To address the complex and unsettled debate on grading laryngopharyngeal pre-

malignant mucosal lesions, a two-tiered grading system was adopted [3, 4]. However, the three-

tiered grading system for malignant lesions of the oval cavity (including tongue) remained

unchanged. Although major efforts were exercised to avoid significant alterations and deletions

of existing entities, few modifications were made where a consensus was reached. These included

the deletion of the qualifier “low grade” from the diagnosis of "polymorphous low grade
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adenocarcinoma" [5, 6]. The justification for this deletion was based on the reported aggressive

behavior of some of these tumors and to allow for the inclusion of these patients in therapeutic

trials of advanced salivary cancers. Similarly, acantholytic squamous cell carcinoma was deleted

as a subtype based on a consensus that it merely represents a morphologic feature of keratinizing

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squamous cell carcinomas.

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Importantly, two new chapters were introduced; one for the oropharynx through its

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segregation from the original oral cavity and the other for the neck region. The introduction of

the oropharyngeal chapter was unanimously approved in recognition of the unique anatomic

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and histologic characteristics and the strong association with HPV for carcinoma occurring at this
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location. The new chapter for the neck was created in acknowledgement of the importance of

primary metastatic and developmental pathologies of this region [7-10]. It was also felt that the
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initial presentation of a variety of developmental, reactive and acquired tumor-like lesions is

important in the differential diagnosis of tumors at this location. Moreover, the accessibility of
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the neck structures to fine needle aspirations and direct or CT-guided core biopsies allow for

effective and initial pathologic assessment diagnostic tools [11-15]. Also, in this edition, fine
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needle aspiration cytologic features were included especially in salivary gland and neck lesions. The
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editors also considered the procedure critical not only for diagnosis and follow up of treated

patients but also a source of materials for genomic testing.

New tumor entities with consensus on their diagnostic and clinical relevance have been

included. This was based on proven documentation of their unique characteristic groups and their

diagnostic and clinical relevance. Among these are NUT carcinomas [16-18] and biphenotypic

sinonasal sarcoma [19, 20]. Among salivary gland tumors, secretory carcinoma (mammary

analogue secretory carcinoma) was introduced as a new entity [21, 22]. Consideration to

create new entities that currently represent a subtype of an established tumor such as

cribriform adenocarcinoma as a separate from a polymorphous adenocarcinoma was deferred

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pending further studies to validate their potential inclusion as new entities. HPV-associated

carcinoma with adenoid-cystic like features as a variant of non-keratinizing squamous cell

carcinoma was recognized as a provisional entity. Another notable modification in chapter 7

includes the requirement to specify the type of carcinoma evolving from pleomorphic adenoma.

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In this 4th edition, nomenclature of soft tissue, neuroendocrine and lymphoreticular

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neoplasms was harmonized with similar entities in other WHO tumor classifications books. In

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that context, current classification of neuroendocrine carcinomas into low (carcinoid),

intermediate (atypical carcinoid) and high grade (poorly differentiated small and large cell)

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carcinomas paralleled the terminology used in other organs. Notable broad categorizations were
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made in which paraganglioma is considered a malignant entity and thereby nullifying the need

for additional descriptive terms and sialoblastoma was re- classified as malignant based on
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sufficient documentation of their aggressive nature. In addition, rarely encountered morphologic

variants of salivary adenocarcinomas including cribriform, micro-papillary and intestinal-type

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adenocarcinomas were grouped under adenocarcinoma NOS [23-26].

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Efforts were particularly made to simplify the categorization of odontogenic tumors and

lesions. Accordingly, the terms ameloblastic carcinoma, and odontogenic sarcomas were retained
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while all other descriptive terms including primary, differentiated, and malignant descriptive

terms were omitted. Multiple entities were omitted including ameloblastic fibro- dentinoma,

fibro-odontoma and odontoameloblastoma due to the uncertain nature and lack of clinical

relevance. A consensus was researched to re-classify keratocystic odontogenic tumor and the

calcifying cystic odontogenic tumor as cysts, considering the clinical non-neoplastic behavior of the

majority of these lesions. New neoplastic entities were also introduced including sclerosing

odontogenic carcinoma, odontogenic carcinosarcoma, primordial odontogenic tumor.

Odontogenic and non-odontogenic cysts were revived for their differential diagnostic relevance.
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Given the economic constrains and limited accessibility to ancillary techniques in

world geographic regions, the term “not otherwise specified” was retained for entities that can

further be characterized by either lineage based or biological-genetic markers in advanced

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centers. In addition, new and emerging molecular-genetic and biomarkers have sufficiently

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been discussed with the caveat that their diagnostic utility has yet to be clinically validated for

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routine pathology practice.

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References:

1. El-Naggar AK, Chan J, Takata T, Grandis J, Blootweg P (2017) WHO Classification of tumors,
Pathology and Genetics of Head and Neck Tumors 3rd Edition Lyon: IARC Press

2. Barnes L., Eveson JW, Reichart P, Sireansky D. Editors (2005) WHO Classification of tumors,

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Pathology and Genetics of Head and Neck Tumors 3rd Edition Lyon: IARC Press

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3. Fleskens S., Slootweg P. (2009) Grading systems in head and neck dysplasias: their
prognostic value, weakness and utility. Head and neck oncology 1:11

SC
4. Gale N., Blagus R, GL-Mofty SK, Hell:Well T, Prasad ML, Sandson A et al (2014). Evaluation of
new grading system for laryngeal squamous intraepithelial lesions – a proposed useful

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classification. Histopathology 65: 456-464.

5. Kimple AJ, Austin GK, Shah RN, Welch CM, Funkhouser WK, Zanation AM et al (2014).
MA
Polymorphous low grade adenocarcinoma: A case series and determination of recurrence
laryngoscope 124: 2714-2719.

6. Patel TD, Vazquez A, Marchiano E, Park RC, Barendas S, Eloy JA (2016). Polymorphous low
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grade carcinoma of the head and neck: A population-based study of 460 cases.
Laryngoscope 125:1644-1649.
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7. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH,
Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. Human
papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010 Jul 1;
CE

363(1):24-35. doi: 10.1056/NEJMoa0912217. PubMed PMID: 20530316; PubMed Central

PMCID: PMC2943767.
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8. Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, Jiang B, Goodman MT,
Sibug-Saber M, Cozen W, Liu L, Lynch CF, Wentzensen N, Jordan RC, Altekruse S, Anderson
WF, Rosenberg PS, Gillison ML. Human papillomavirus and rising oropharyngeal cancer
incidence in the United States. J Clin Oncol. 2011 Nov 10;29(32):4294-301. doi:
10.1200/JCO.2011.36.4596. PubMed PMID: 21969503; PubMed Central PMCID:
PMC3221528.

9. Gillison ML, Zhang Q, Jordan R, Xiao W, Westra WH, Trotti A, Spencer S, Harris J, Chung CH,
Ang KK. Tobacco smoking and increased risk of death and progression for patients with
p16-positive and p16-negative oropharyngeal cancer. J Clin Oncol. 2012 Jun
10;30(17):2102-11. doi: 10.1200/JCO.2011.38.4099. PubMed PMID: 22565003; PubMed
Central PMCID: PMC3397696.

10. Lechner M, Frampton GM, Fenton T, Feber A, Palmer G, Jay A, Pillay N, Forster M, Cronin MT,
Lipson D, Miller VA, Brennan TA, Henderson S, Vaz F, O'Flynn P, Kalavrezos N, Yelensky R,
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Beck S, Stephens PJ, Boshoff C. Targeted next-generation sequencing of head and neck
squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors.
Genome Med. 2013 May 29;5(5):49. doi: 10.1186/gm453. PubMed PMID: 23718828;
PubMed Central PMCID: PMC4064312.

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11. Ferlito A., Bertino G., Rinaldo A., Mannara GM., Deneng KO (1999). A review of heterotopia

P
and associated salivary glands neoplasms of the head and neck. J laryngol otol 113:299-303.

RI
12. Klubo-Gwiezdzinska J., Manes RP., Chia SH., Buman KD, Stathatos NA., Deeb ZE, et al (2011).
Clinical review: Ectopic cervical thyroid carcinoma: A review of the literature with

SC
illustrative case services. J. Clin Endocrinal Metab. 96: 2684-2691.

13. Golledge J., Ellis H., (1994). The etiology of lateral cervical (branchial) cysts: past and

NU
present theories. J. laryngeal Otol 108:653-659.

14. La Plante JK., Person NS., Hedlund GL. (2015) Common pediatric head and neck
MA
congenital/developmental anomalies. Radiol Clin North Am 53:181-196.

15. Garu C., Johansen LV., Jacobsen J., Gertsen P., Andersen E., Jensen BB (2000). Cervical lymph
ED

node metastasis from unknown primary tumors. Results from a national survey by the
Danish Society for head and neck oncology. Radiother Oncol 55: 121-129.
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16. Barnes DE, Mitchell CM, Strait KM, Lahan CS, Stelow EB, Luer SC et al (2012:
Clinicopathologic features and long term outlines of NUT midline carcinoma. Clin Cancer
Chan NG, Mitchell CM, Asterlind A, Granfeld N, Kaplan L, Lathan CB, et al (2014 Aggressive
CE

treatment and survival outcomes in NUT Midline Carcinoma (NMC) of the head and neck. J
clin Oncol 2014, Suppl 22, 6057. Res 18:5773-5779.
AC

17. Chan NG, Mitchell CM, Asterlind A, Granfeld N, Kaplan L, Lathan CB, et al (2014 Aggressive
treatment and survival outcomes in NUT Midline Carcinoma (NMC) of the head and neck. J
clin Oncol 2014, Suppl 22, 6057.

18. Haack H, Johnson LA, Fry CJ, Cosby K, Polakewicz RD, Stelow EB et al (2009) Diagnosis of
NUT midline carcinoma using a NUT-specific monoclonal antibody. Am J Surg Path 33:984-
991.

19. Huang SC, Ghossin BA, Bishop JA, Zhang L, Chan TC, Huang HY et al (2016) Novel PAX3-
NCOA1 fusion in biphenotypic sinonasal sarcoma with focal rhabdomyoblastic
differentiation. Am J Surg Pathol 40:51-59.

20. Lewis JT, Oliveria AM, Nascimento AG, Schembri-Wismayer D., Moore EA, Olsen KD et al
(2012) low-grade sino-nasal sarcoma with neural and myogenic features: A clinic-
pathologic analysis of 28 cases. Am J Surg Pathol 36:517-525.
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(John CHAN Kwok-cheung)

21. Reis-Filho JS, Natrajan R, Valcheva R. et al (2008). Is Acinic cell carcinoma a variant of
secretory carcinoma? A FISH study using ETV6 split a part probes. Histopathology 52: 840-
846

T
22. Kalova A. Vancek T., Sima R., Laco J., Weinreb J, Perez-Ordonez B, et al (2010). Mammary

P
analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: A
hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 34:599-608.

RI
23. Nagao T, Gaffey TA, Vischer DW, Kay PA, Minato H, Serizawa H. et al (2004). Invasive

SC
micropapillary salivary duct carcinoma: A distinct histologic variant with biologic
significance. Am J Surg Pathol: 28:319-326.

NU
24. Bell D., Kupferman ME., Williams MD., Rashid A., El-Naggar AK (2009). Primary colonic-type
adenocarcinoma of the base of tongue: A previously unreported phenotype. Ham Pathol 40:
1798-1802.
MA
25. Gillenwater AM., Fatani H., El-Naggar AK. (2013) Primary intestinal-like adenocarcinoma of
major salivary glands: 2 instances of previously undocumented phenotype. Head and neck
ED

35: E234-236.

26. Spiro RH., Huvas AG, Strong EW (1982) Adenocarcinoma of salivary origin.
PT

Clinicopathologic study of 204 patients. Am J Surg 144: 423-441.

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Response to Reviewers
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Response to editor comment #1:

There is no 2010 edition

Response to editor comment #2:

References #16-18 are cited

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Response to editor comment #3:
Abbreviations have been defined

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Response to editor comment #4:

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In-text citations are formatted with square brackets to the left of punctuation.

Response to editor comment #5:

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Author information has been submitted.
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